Pinkal Desai, MD, Weill Cornell Medicine, New York City, New York, discusses challenges within the current treatment options for patients with secondary acute myeloid leukemia (AML), such as liposomal daunorubicin with cytarabine (CPX-351) and hypomethylating agents (HMA) in combination with venetoclax, and the need for stronger therapies for this disease subset.

Dr Desai explained the general response rate is only in the matter of 6 to 9 months with CPX-351 treatment, and the average survival is under 1 year for patients treated with HMA and venetoclax.

 This research was presented at the 2024 Annual Society of Hematologic Oncology (SOHO) meeting in Houston, Texas.

Transcript:

Hello, I'm Pinkal Desai. I am an associate professor of medicine and a leukemia physician at Weill Cornell Medicine in New York. I'm here at [the 2024 Society of Hematology Oncology meeting] (SOHO) where I will be giving a talk on what is the best therapy for secondary acute myeloid leukemia.

To define what secondary AML stands for, there are several categories that are relevant here. First is when AML happens because of prior exposure to chemotherapy and or radiation, which is the therapy-related AML. Also, when AML occurs from a pre-existing myeloid disorder like [myelodysplastic syndrome] (MDS) or myeloproliferative neoplasms (MPNs). That is sort of the true secondary AML. Both are very challenging diseases to treat for many reasons. First [are] the biological [reasons]. Biologically, these leukemias are more adverse risk. They have worse cytogenetics and mutations like TP53 mutations. Secondly, these patients generally tend to have more comorbidities having been exposed to previous chemotherapy, [and potentially] more organ dysfunction. And more importantly for the secondary AML category, they may have had exposures to hypomethylating agents (s), which as we know are an important part of our frontline treatment, particularly in older patients who cannot tolerate intensive chemotherapy.

For all these reasons, these groups of AMLs are challenging. So, what do we currently treat them with? Overall, the general strategy is to get these people into remission and if they're transplantable, then [proceed with] transplant and then [have them] put on some kind of maintenance. Post-transplant maintenance in this setting is not completely randomized [given] clinical trial data driven options, but for those that do not get transplanted, certainly maintenance is relevant.

So, taking a step back in terms of therapy-related AML, what do we consider therapy related? Is it chemotherapy exposure, radiation therapy exposure? I'm going to show data that suggests just having radiation therapy alone may not actually behave like a true therapy-related AML in terms of prognosis and survival. For the most part, when we suggest therapy-related AML, we're really talking about chemotherapy-exposed patients. We also [are] not talking about therapy-related diseases that are good risk. There are some people who can have NPM1 mutations or inv(16) or core binding factor leukemia and sometimes, rarely, even [acute promyelocytic leukemia] APL can emerge in the realm of therapy-related diseases.

These are generally good risk, and they retain their good risk nature. Those are treated mostly like good risk leukemia. I'm really talking about the other category, which is generally intermediate or adverse [European Leukemia Net] ELN risk. It's important to note that therapy relatedness or secondary leukemias do not have a separate category in the ELN risk. They are sort of like an addendum or a secondary addition. And the current stratification of ELN risk is based on cytogenetics and molecular features, irrespective of whether they're therapy-related or secondary AML.

Are they important? Yes, because a lot of these are exposed to hypomethylating agents. They are more adverse risk, but not only are they adverse, they have previous chemotherapy or even hypomethylating drug exposure. When we think about ELN risk, all of that is based on people who are treated with intensive chemotherapy. These patients who have these prior exposures are quite difficult to treat and our current options of treatments do not address the need that we have for these patients.

What are our current options? Liposomal daunorubicin and cytarabine, or CPX-351, is the standard therapy for people who are in this category and have organ function that's adequate [and] they are intensive chemo eligible. The general response rate, although is about a complete remission rate of 30% to 40% and the median survival of these people, particularly the ones that were exposed to prior HMA, is only in the matter of 6 to 9 months. So, we really do need better therapies.

The second category that we have is HMA in combination with venetoclax, which we generally use in people who are not intensive chemo eligible. In some patients who are biologically adverse risk, [this] might be used even in younger patients. Also, because of the higher presence of TP53 mutations and many times even the RAS mutations that are known to be something that venetoclax doesn't work against well, they tend to not be the people who are in remission for many years. The average survival in this group, even with HMA and venetoclax treatment is well under 1 year. For TP53 mutations, it's almost not clear whether venetoclax is adding and several studies have come forward that have suggested that there is no improvement in survival with the addition of venetoclax to a HMA backbone on top of it. If they have already seen hypomethylating agents in the past for their MDS or MPN, then they're more likely to be refractory. So, this is a big unmet need.

The other category, which we don't talk about so much is [chronic myelomonocytic leukemia] CMML and MPN that then converts to AML. These are profoundly difficult diseases to treat, maybe [they are] primary refractory and have several other issues like splenomegaly and lots of constitutional symptoms that come with their AML diagnosis that are difficult to handle. It is also difficult to transplant these [patients] because of the same reason; they have big spleens [and there is] worry about potentially graft failure for these patients. Yet what has been shown [is] that if we are able to get these people into remission and then transplant, the survival seems to be better. The problem is we don't have great drugs to get these people into good remission prior to going into transplant.

Now, there is hope within this category of therapy and secondary AML. We have the KMT2A-rearranged AML where the menin inhibitors are currently undergoing clinical trials and those are drugs that have shown single agent responses to these KMT2A-rearranged AML. The problem is it doesn't last long, so I think the answer lies in combination therapy [and] moving [patients] in the frontline setting and then giving the approach of treating with the combination therapy, getting [patients] into remission, and then going for maintenance.

A lot of these trials are designed in that sort of [] complete sweep at induction, transplant, remission, and post remission maintenance. That's what we really [must] do to move the needle for these secondary AML [treatments]. It is not [to] just get into remission and forget about it. There's going to have to be strategies in almost every aspect of AML management to get more people across the finish line and getting them cured from this disease.

Source:

Desai P. Secondary AML - Best therapy. Presented at the 2024 Society of Hematologic Oncology meeting. Houston, Texas; September 4-7, 2024.